Panum - instructions for use, description, questions about the drug

Instructions for use PANTASUN tablets

Before starting treatment, it is necessary to exclude the possibility of a malignant process (especially with a stomach ulcer), because Treatment with pantoprazole may mask symptoms and delay correct diagnosis.

During long-term treatment with pantoprazole (1 year or more), patients should be monitored regularly.

There have been reports of the development of symptomatic and asymptomatic hypomagnesemia in patients taking proton pump inhibitors for at least 3 months, in most cases after 1 year of therapy. Serious side effects include tetany, arrhythmia, and seizures. Most patients required administration of magnesium salts and discontinuation of proton pump inhibitors. If long-term use of proton pump inhibitors or concomitant use of digoxin or other drugs that can cause a decrease in magnesium levels (for example, diuretics) is planned, it is necessary to determine the level of magnesium in the blood serum before starting the use of proton pump inhibitors and periodically during therapy.

Research data suggests that the use of proton pump inhibitors may be associated with an increased risk of fractures of the hip, wrist, and spine. The risk of fractures was increased in patients who received high doses of proton pump inhibitors (multiple daily doses) and/or long-term therapy (1 year or more). It is recommended to take proton pump inhibitors in the minimum therapeutic dose in accordance with the indications for use, the duration of treatment should be minimal. Patients at risk for fractures should be treated according to established guidelines.

In patients with severe liver dysfunction, pantoprazole is prescribed with caution. The recommended dose is 20 mg 1 time / day or 40 mg 1 time every 2 days (under the control of biochemical blood parameters). If the activity of liver enzymes increases, the use of the drug should be discontinued.

Patients with severe liver failure or renal failure should not be prescribed the drug in combination to eradicate H. pylori, since there is insufficient experience with such treatment in patients in these groups.

Patients with severe liver failure and patients with impaired renal function are not recommended to prescribe the drug at a daily dose higher than 40 mg. An exception is combination antimicrobial therapy against H. pylori, when patients need to take pantoprazole at a dose of 40 mg 2 times a day.

Use in pediatrics

There is no clinical experience with the use of pantoprazole in children, therefore the drug is prescribed to children under the age of 12 years

Not recommended.

Impact on the ability to drive vehicles and operate machinery

Pantasan does not affect the ability to drive vehicles and operate machinery. It should be borne in mind that while using the drug, dizziness or blurred vision may occur; in such cases, the patient should refrain from driving a car or using other mechanisms.

Toxicity, embryotoxicity, teratogenicity, mutagenicity, carcinogenicity

In a 2-year carcinogenicity study, rats were administered pantoprazole at doses 4 to 352 times the dose recommended for humans. The formation of gastric carcinoid tumors late in life and dose-dependent hyperplasia of intestinal chromaffin-like cells were observed in both sexes. The latter change is due to an increase in gastrin levels (hypregastrinemia) due to the administration of high doses of an acid inhibitor. The same effect is observed with the use of H2 receptor blockers.

Clinical experience with the drug in pregnant women is limited. Mild cases of fetotoxicity have been reported in animal studies at doses greater than 5 mg/kg. There is no data on the excretion of pantoprazole in breast milk in women.

Panum, 20 mg, enteric film-coated tablets, 28 pcs.

Before starting treatment with Panum®, the possibility of malignancy should be excluded, since the drug may mask symptoms and delay the correct diagnosis.

Patients should consult their physician if they are undergoing an endoscopy or urea breath test.

Patients should consult a doctor if the following occur:

- unintentional weight loss, anemia, gastrointestinal bleeding, difficulty swallowing, persistent vomiting or vomiting blood. In these cases, taking the drug may partially relieve symptoms and delay correct diagnosis;

- previous surgery on the gastrointestinal tract or gastric ulcer;

- continuous symptomatic treatment of dyspepsia and heartburn for 4 weeks or more;

- liver diseases, including jaundice and liver failure;

- other serious diseases that worsen general health.

Patients over the age of 55 who have new or recently changed symptoms should consult a doctor.

Patients should not expect immediate relief from symptoms of illness. Symptom relief may be possible after approximately one day of taking pantoprazole, but it should also be taken into account that it may take approximately 7 days for heartburn to completely resolve.

When taking medications that reduce the acidity of gastric juice, the risk of gastrointestinal infections caused by bacteria of the genus Salmonella spp., Campylobacter spp. slightly increases. or C. difficile.

When treated with proton pump inhibitors, the development of subacute cutaneous lupus erythematosus (SCLE) is very rarely observed. If skin lesions occur, especially in sun-exposed areas, or if there is concomitant arthralgia, the patient should seek immediate medical attention and the physician should evaluate the need to discontinue treatment with Panum®. The occurrence of PCLE after previous treatment with a proton pump inhibitor may increase the risk of developing PCLE when treated with other proton pump inhibitors.

When conducting laboratory tests, it is necessary to take into account that increased levels of CgA in the blood serum may distort the results of diagnostic studies to identify neuroendocrine tumors. In this regard, the use of Panum® should be discontinued at least 5 days before the CgA content study. If CgA and gastrin levels have not returned to normal values after the first determination, the study should be repeated 14 days after stopping the proton pump inhibitor.

The drug is intended for short-term use (up to 4 weeks).

With long-term use of the drug, additional risks may arise, and it is necessary to consult a doctor to prescribe the drug, followed by regular medical supervision.

The following additional risks are considered significant with long-term use of the drug.

Effect on the absorption of Vitamin B12

Pantoprazole, like all proton pump inhibitors, can reduce the absorption of vitamin B12 (cyanocobalamin) as a result of hypo- or achlorhydria. This should be taken into account in patients with reduced body reserves or risk factors for reduced absorption of vitamin B12 during long-term therapy or in the presence of corresponding clinical symptoms.

Effect on bone fractures

Proton pump inhibitors, especially at high doses and during long-term therapy (>1 year), may slightly increase the risk of hip, wrist, and spine fractures, primarily in older adults or those with other known risk factors. Observations have shown that proton pump inhibitors may increase the overall risk of fractures by 10-40%. This increase may be due in part to other risk factors.

Patients at risk of developing osteoporosis should be treated in accordance with current clinical guidelines and should have an adequate intake of vitamin D and calcium.

Hypomagnesemia

Patients taking proton pump inhibitors (PPIs), including pantoprazole, for at least three months and, in most cases, for a year, experienced severe hypomagnesemia. In this case, it is possible to develop severe manifestations of hypomagnesemia, such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia, they can begin unnoticed and be missed. In most patients with such disorders, hypomagnesemia was corrected after magnesium replacement therapy and discontinuation of PPIs.

In patients undergoing long-term treatment or patients taking PPIs concomitantly with digoxin or other drugs that may cause hypomagnesemia (eg, diuretics), serum magnesium levels should be tested before initiating PPI treatment and monitored periodically during treatment. .

Experience with the use of the drug Panum (pantoprazole) in the treatment of erosive and non-erosive esophagitis

The prevalence of gastroesophageal reflux disease (GERD) is high. The leading symptom of GERD is heartburn. The incidence of heartburn in developed countries in Europe and North America is 7.7–27% (8). According to a population study conducted in Novosibirsk, 48.5% of women and 51.4% of men occasionally experience heartburn; 3.7% of women and 1.2% of men often complain of heartburn. Among adolescents aged 14–17 years, heartburn with a frequency of more than once a month was recorded in 16.9%, more than once a week – in 6.7%, and sour belching was recorded in 8.5% of respondents (9). The results of our own studies showed that the prevalence of GERD in gastroenterological patients according to endoscopy was 27.8%, with non-erosive forms observed in 17.4% of cases, erosive esophagitis in 10.4% (1).

Table 1. Number of patients with complete healing of erosions by 4 and 8 weeks of treatment

Table 2. Number of patients with complete relief of heartburn by week 8 of treatment

Table 3. Estimation of serum gastrin 17 levels before and after 8 weeks of course treatment

Table 4. VAS data before treatment, at weeks 4 and 8 of course therapy

Table 5. Data from the SF-36 questionnaire before treatment and by the 8th week of course treatment

Table 6. Data before treatment, at 4 and 8 weeks of maintenance therapy

Table 7. Indicators of the SF-36 questionnaire before treatment and at week 8 of maintenance treatment

Currently, GERD is divided into an endoscopically negative (non-erosive) - NERD - and a positive form (reflux esophagitis and Barrett's esophagus). The diagnostic standard for NERD is clinical symptoms (primarily heartburn) if they lead to a clinically significant decrease in quality of life.

Today, the most common approach to the treatment of reflux disease is the prescription of proton pump inhibitors (PPIs) in different versions (continuous, course and maintenance, symptomatic). This group of drugs has been used to treat GERD since the 1980s. During clinical use, it was shown that PPIs are superior to H2-blockers in the effectiveness of healing of erosive esophagitis, and maintenance use can significantly reduce the frequency of disease relapses. Today, there are 5 PPIs on the domestic pharmaceutical market: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole and Esomeprazole.

Selecting a drug from the PPI group poses certain difficulties due to their wide variety and conflicting data on their comparative effectiveness. The differences between them are determined by the speed and duration of the acid-blocking effect, as well as the effect on the metabolism of other drugs that “pass” through the cytochrome P450 system.

Under the influence of PPIs, the proton pump is inactivated, but then its activity returns to its previous level (2). After taking Lansoprazole, the half-life of recovery of acid production is 12.9 hours; Omeprazole and Rabeprazole – 27.5 hours, and Pantoprazole – 45.9 hours (3). The difference in the duration of inhibition is due to differences in the duration of retention of PPI bonds with cysteine residues of ATPase. Omeprazole and other drugs interact with cysteine residues at position 813, Lansoprazole - with cysteine 321, Pantoprazole - with cysteine 822. Cysteine 822 ensures binding stability, therefore, when using Pantoprazole, the secretion of hydrochloric acid is resumed mainly due to the synthesis of ATPase, and not due to the destruction of the chemical connection between the PPI and the proton pump. Thus, the duration of effect of Pantoprazole is longer than that of other PPIs (4).

Metabolism of all PPIs occurs in the liver with the participation of cytochrome P450. Most PPIs inhibit the metabolism of many drugs, such as Diazepam, Phenytoin, Warfarin, β-blockers, Digoxin, Theophylline, Diclofenac, Clarithromycin, Clopidogrel, etc. (5). If it is necessary to take several drugs in combination, it is advisable to use PPIs with minimal effect on microsomal enzymes of hepatocytes. Pantoprazole is superior to other PPIs in this regard, as demonstrated in a study by DN Juurlink et al (6). They conducted a population-based case-control cohort study over a 5-year period among patients aged 66 years or older who started clopidogrel after hospital treatment for acute myocardial infarction. The study included patients who were readmitted to the hospital with acute myocardial infarction within 90 days of discharge.

Among 13,636 patients receiving clopidogrel after acute myocardial infarction, 734 cases with rehospitalization with myocardial infarction and 2057 control cases were identified. In an expanded multivariate analysis, there was an association between current use of proton pump inhibitors and an increased risk of recurrent infarction (adjusted odds ratio (OR) 1.27, 95% confidence interval (CI) 1.03–1.57). In the stratification analysis, Pantoprazole, which does not inhibit cytochrome P450 2C19 was not associated with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70–1.47).

Among patients receiving clopidogrel after acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a decrease in the beneficial effects of clopidogrel and an increased risk of recurrent infarction (6).

The experience of using Pantoprazole in our country is currently limited. For this reason, we assessed the effectiveness and safety of a course of therapy with Panum (Pantoprazole) (Unique Pharmaceutical Laboratories, Department, India) in patients with erosive and non-erosive forms of GERD for 8 weeks and maintenance therapy for 8 weeks.

Materials and methods

The effectiveness of a course of therapy with Panum (Pantoprazole) 40 mg per day was assessed based on the number of patients with complete healing of erosions and complete relief of heartburn by the 8th week of therapy. The effectiveness of maintenance therapy with Panum (Pantoprazole) 40 mg every other day for non-erosive and erosive reflux disease for 8 weeks was assessed by the number of patients who maintained clinical and endoscopic remission. The safety assessment of the drug was based on the registration of adverse events and side effects.

Additional objectives of the study were: to assess the healing of erosive esophagitis by the 4th week of treatment; assessment of serum gastrin levels before and after 8 weeks of course treatment; study of the level of quality of life according to the visual analogue scale and the SF 36 questionnaire before and after a course and maintenance treatment.

The study included patients with GERD grades 0–4 according to the Savary–Miller classification, who had heartburn of varying severity before treatment and met the inclusion and exclusion criteria.

Inclusion criteria:

Male or female patients over the age of 18 who voluntarily signed informed consent. Women must be menopausal or using a method of contraception that is considered reliable by the investigator during the trial.
Patients who have experienced heartburn as the main symptom of the disease for at least 12 months, with at least 2 episodes of symptoms (including symptoms before treatment).
Patients with GERD grades 1–4 according to the Savary–Miller scale during EGD.
Patients with no erosive changes in the esophageal mucosa, but who reported moderate or severe heartburn (≥ 2 points on the Likert scale) at least 1 time during the week preceding course therapy and with the presence of pathological acid exposure in the lumen of the esophagus according to 24-hour criteria intraesophageal pH-metry.

Exclusion criteria:

Patients who are unable or unwilling to make all necessary doctor visits.
Patients with exacerbation of gastric or duodenal ulcers, infectious or inflammatory diseases of the small or large intestine, impaired intestinal absorption, intestinal obstruction; with malignant diseases of the gastrointestinal tract or a history of surgical interventions on the stomach or intestines.
Patients testing positive for H. pylori. *
Patients with scleroderma.
Patients with severe concomitant diseases of the cardiovascular system, respiratory system, kidneys and liver, with mental illness, with malignant diseases or HIV infection.
Pregnant women or women planning pregnancy during this study.
Working at night.
Patients who have abused alcohol or drugs in the past (within the last 5 years) or currently.
Patients who are taking and will not be able to stop taking anticholinergic, cholinergic, antispasmodic drugs, H2 blockers, opiates, sucralfate.
Patients regularly taking NSAIDs (non-steroidal anti-inflammatory drugs), oral steroid hormones or aspirin (> 325 mg/day).
Patients with a non-erosive form of the disease and normal 24-hour pH measurements (patients with functional heartburn).
Patients with Barrett's esophagus.

Statistical processing of the results was carried out using statistical analysis programs Statistica 6. Descriptive statistics are presented in the form of average values and their standard deviation (M±SD). Comparisons of average values were carried out using the Student's t-test; differences at the p level were taken as statistically significant

If all inclusion and exclusion criteria were met, the patient entered the treatment period. At the second visit (day 1 of treatment), the patient was given the drug for 28 days of treatment and instructions for its use. During the entire treatment period, patients recorded in an individual diary the presence and severity of symptoms (heartburn and acid regurgitation) during the day and night, as well as the use of additional medications (antacids) if heartburn persisted. At all follow-up visits (28, 56, 84 and 112 days), a physical examination and assessment of the severity of symptoms, registration of adverse events and side effects, as well as endoscopy were performed to assess the degree of inflammatory changes in the esophageal mucosa. Quality of life assessment according to VAS and SF-36 questionnaire was carried out on days 56 and 112 of treatment.

Research results

30 HP-negative patients (20 men, 10 women) were accepted for the study. Average age 45.6±2.8 years. The degree of erosive esophagitis was determined according to the Savary–Miller classification. Depending on the degree of GERD, patients were distributed as follows: 0th degree - 5, 1st degree - 15, 2nd degree - 5, 3rd degree - 2, 4th degree - 3 people.

Evaluation of effectiveness in the treatment of grade 0–4 erosive esophagitis based on the number of patients with complete healing of erosions by the 4th and 8th weeks of therapy

The results of endoscopy data at the 4th and 8th week of treatment for patients with erosive esophagitis are presented in Table 1.

When treating 25 patients with erosive esophagitis, 2 patients dropped out due to the development of side effects. Thus, the analysis of the results was carried out: – in a group of 25 patients according to the “intention to treat” (ITT – intent-to-treat); – in a group of 23 patients who completed this part of the study “per protocol” (PP – per protocol).

As can be seen from the presented data, in the ITT analysis, the healing rate by the 4th and 8th weeks of therapy was 84% and 88%, respectively. When analyzing PP, the effectiveness of therapy according to endoscopy by the 4th and 8th weeks of treatment was 91.3% and 95.6%, respectively. Healing of erosions could not be achieved in 1 patient with grade 4 erosive esophagitis.

Evaluation of effectiveness in the treatment of GERD based on the number of patients with complete relief of heartburn by the 8th week of therapy

The results of studying the number of patients with complete relief of heartburn by the 8th week of treatment are presented in Table 2.

In the ITT analysis, complete relief of heartburn out of 30 patients with erosive and non-erosive forms of GERD was achieved in 86.6%. When analyzing RR, heartburn was completely relieved in 92.9% of cases, in 2 patients mild heartburn remained: in 1 patient with grade 4 erosive esophagitis and persistence of erosions by the 8th week of course therapy and in 1 patient with complete healing of erosions by the end of the course therapy, according to the individual diary, heartburn also persisted.

Assessment of serum gastrin levels before and after 8 weeks of course treatment

Gastrin concentrations were determined using an automatic chemiluminescence immunoassay analyzer Immulite2000 (DPC, USA). The method allows you to determine with high accuracy the level of gastrin 17, but not other molecular forms of gastrin (big and big-big gastrin). The results of determining the level of serum gastrin 17 before and after 8 weeks of therapy with Panum are presented in Table 3.

The differences were significant, Student's test was 3.5; p = 0.001.

Thus, treatment for 8 weeks led to an increase in the level of serum gastrin 17 by more than 2 times. These data indirectly reflect the effective acid suppression under the influence of therapy with Panum.

Evaluation of the effectiveness of course therapy based on the results of studying VAS data and the SF-36 questionnaire

The dynamics of VAS data are presented in Table 4.

The presented data indicate a significant increase in the quality of life according to VAS data already by the 4th week of treatment and its improvement by the 8th week of therapy. The results of studying the data from the SF-36 questionnaire are presented in Table 5.

The 36 items of the questionnaire are grouped into eight scales: physical functioning, role functioning, bodily pain, general health, vitality, social functioning, emotional state and mental health. Scores on each scale range between 0 and 100, with 100 representing complete health, such that a higher score indicates a higher level of QoL.

After 8 weeks of therapy with Panum, there was a significant improvement in physical functioning; role functioning due to physical condition; pain intensity; vital activity; social functioning; role functioning due to emotional state; mental health. The consequence of this was a significant improvement in the physical (Physical health - PH) and psychological (Mental Health - MH) components of health (Table 5).

Evaluation of the effectiveness of maintenance therapy for non-erosive and erosive reflux disease based on the number of patients with complete relief of heartburn by the 4th and 8th weeks of maintenance therapy

By the 4th week of maintenance therapy, recurrence of heartburn was noted by 4 (14.8%) patients out of 27 patients who continued the study. Relapse occurred in patients with erosive esophagitis. In two patients, heartburn was mild, not daily, and amounted to 4 and 5 points according to the calculated indicator. Thus, by the 4th week of maintenance therapy, its effectiveness was 85.2%.

The final assessment of effectiveness by the 8th week of maintenance treatment was as follows: relapse of symptoms was observed in 4 patients (14.8%), relapse of erosive esophagitis was observed in 5 patients (18.5%). The overall effectiveness of 8-week maintenance therapy, taking into account both the clinical and endoscopic picture, was 77.8%.

Evaluation of the effectiveness of maintenance therapy based on the results of studying data from the VAS and the SF-36 questionnaire.

The dynamics of VAS data are presented in Table 6.

The presented data indicate that a significant increase in the quality of life according to VAS obtained after a course of therapy was maintained during maintenance treatment. The results of studying the data from the SF-36 questionnaire are presented in Table 7.

Positive changes in quality of life according to the SF-36 questionnaire obtained after a course of therapy persisted after 8 weeks of maintenance treatment.

The safety assessment of the drug Panum (Pantoprazole) at a dose of 40 mg per day is based on the registration of adverse events and side effects in all treated patients.

The safety assessment was the frequency of adverse events assessed according to the following criteria: severity, severity, relationship between the side effect and the study drug, outcome and measures taken.

No serious adverse events were noted during the study. Side effects in the form of abdominal pain were observed in 3 patients; in 2 cases the drug was discontinued. In one patient, the pain was mild and went away on its own after reducing the dose when transferring him to maintenance treatment.

Conclusion

A course of treatment with Panum at a dose of 40 mg per day in patients with degrees 1–4 erosive esophagitis was highly effective: in the ITT analysis, the healing rate by weeks 4 and 8 of therapy was 84% and 88%, respectively. When analyzing the RR, the effectiveness of therapy according to endoscopy at 4 and 8 weeks of treatment was 91.3% and 95.6%, respectively. Healing of erosions could not be achieved only in 1 patient with grade 4 erosive esophagitis.

An assessment of the clinical effectiveness of the drug Panum showed that the drug effectively relieves heartburn: in the ITT analysis, complete relief of heartburn out of 30 patients with erosive and non-erosive forms of GERD was achieved in 86.6%. When analyzing the RR, heartburn was completely relieved in 92.9% of cases, in 2 patients mild heartburn persisted.

A course of treatment with Panum led to a significant increase in the quality of life according to VAS data already by the 4th week of treatment and its improvement by the 8th week of therapy. A significant increase in quality of life according to VAS, obtained after a course of therapy, persisted during maintenance treatment.

After a course of therapy with Panum, there was a significant improvement in the following indicators of the SF 36 questionnaire: physical functioning; role functioning due to physical condition; pain intensity; vital activity; social functioning; role functioning due to emotional state; mental health. The consequence of this was a significant improvement in the physical and psychological components of health. Positive changes in quality of life according to the SF-36 questionnaire obtained after a course of therapy persisted after 8 weeks of maintenance treatment.

Evaluation of the effectiveness of maintenance treatment with Panum at a dose of 40 mg every other day for 8 weeks showed that relapse of symptoms was observed in 4 patients (14.8%), relapse of erosive esophagitis was observed in 5 patients (18.5%). The overall effectiveness of 8-week maintenance therapy, taking into account both the clinical and endoscopic picture, was 77.8%. Thus, maintenance treatment at the indicated dose was quite effective.

Treatment for 8 weeks led to a significant increase in the level of serum gastrin 17 by more than 2 times, which indirectly reflects the effective acid suppression during treatment with this drug.

The results of this study confirm the high clinical effectiveness of Pantoprazole in the treatment of patients with various forms of GERD. A recent population-based study showed that the use of Pantoprazole at a dose of 40 mg per day was significantly more likely to lead to a decrease in complaints after 28 days of treatment than the use of Esomeprazole at the same dose (7). Additional advantages of Pantoprazole are: long-term suppression of acid production, which makes it safe to skip the next dose of the drug; low affinity for cytochrome P450, allowing the necessary concomitant therapy to be carried out effectively and safely.

* if HP was detected and the patient consented, a course of eradication therapy was carried out for 2 weeks, followed by a control study for HP 4 weeks after the end of the eradication course; If eradication therapy was effective, the patient was accepted into the study.

Panum®